Selective reductions of cyclic 1,3-diesters by using SmI2 and H2O

Article abstract of DOI:10.1002/chem.201000632

SmI₂/H₂O reduces cyclic 1,3-diesters to 3-hydroxyacids with no over reduction. Furthermore, the reagent system is selective for cyclic 1,3-diesters over acyclic 1,3-diesters, and esters. Radicals formed by one-electron reduction of the ester carbonyl group have been exploited in intramolecular additions to alkenes. The ketal unit and the reaction temperature have a marked impact on the diastereoselectivity of the cyclizations. Cyclization cascades are possible when two alkenes are present in the starting cyclic diester and lead to the formation of two rings and four stereocenters with excellent stereocontrol.

Full text of DOI:10.1002/chem.201000632

DOI: 10.1002/chem.201000632
Selective Reductions of Cyclic 1,3-Diesters by Using SmI2 and H2O
Karl D. Collins,[a] Juliana M. Oliveira,[a] Giuditta Guazzelli,[a] Brice Sautier,[a]
Sara De Grazia,[a] Hiroshi Matsubara,[b] Madeleine Helliwell,[a] and David J. Procter*[a]
Abstract: SmI2/H2O reduces cyclic 1,3-
diesters to 3-hydroxyacids with no over
reduction. Furthermore, the reagent
system is selective for cyclic 1,3-di-
esters over acyclic 1,3-diesters, and
esters. Radicals formed by one-electron
reduction of the ester carbonyl group
have been exploited in intramolecular
additions to alkenes. The ketal unit and
the reaction temperature have
marked impact on the diastereoselec-
tivity of the cyclizations. Cyclization
cascades are possible when two alkenes
are present in the starting cyclic diester
and lead to the formation of two rings
and four stereocenters with excellent
stereocontrol.
a
Keywords: chemoselectivity · cycli-
zation · radical reactions · reduc-
tion · samarium
Introduction
carbonyl group have been exploited in intramolecular addi-
tions to alkenes.
The re-routing of fundamental chemical transformations
through less-conventional intermediates opens up unex-
plored reaction space where new selectivity and reactivity
may be found. For example, our recent studies on the use of
Results and Discussion
[1]
SmI2 as a reductant for the carbonyl group, led us to iden-
In our search for selective reductions using SmI2/H2O we
found the reagent system reduces cyclic 1,3-diesters to the
corresponding 3-hydroxy acids. Cyclic 1,3-diesters, in partic-
ular Meldrumꢀs acid (2,2-dimethyl-1,3-dioxane-4,6-dione),
are versatile building blocks for synthesis.[4] Cyclic 1,3-di-
esters 1a–h are reduced with SmI2/H2O to give the corre-
sponding hydroxy acids 2a–h in good yield (Table 1). No
over-reduction is seen even in the presence of excess re-
agent (see below). As many cyclic 1,3-diesters are conven-
iently prepared by Knoevenagel condensation followed by
conjugate reduction,[4] we have carried out the sequential re-
duction of condensation products 1i and 1j obtaining the
expected products 2 f and 2d in good yield. Finally, reduc-
tion of cyclopropane derivative 1k results in sequential frag-
mentation/carbonyl reduction to give 2k. To our knowledge,
these are the first examples of the mono-reduction of such
systems. The transformation is normally achieved in multiple
steps (e.g. conversion to the monoacid, activation of the acid
as a mixed anhydride, reduction using NaBH4, and hydroly-
sis).[5]
tify SmI2/H2O as a reagent system that not only differenti-
ates between the carbonyl groups of esters and lactones, but
also shows ring-size selectivity for six-membered lactones.[2]
Experimental and computational studies suggested this new
selectivity arose from optimal anomeric stabilization of a
radical anion intermediate in the reduction of six-membered
lactones.[2]
Here we report in full our studies on the mono-reduction
of cyclic 1,3-diesters with SmI2/H2O.[3] The reagent system is
selective for cyclic 1,3-diesters over acyclic 1,3-diesters, lac-
tones and esters and experimental and computational stud-
ies have been used to understand the selectivity. The radical
intermediates formed by one electron reduction of the ester
[a] K. D. Collins, J. M. Oliveira, Dr. G. Guazzelli, B. Sautier,
S. D. Grazia, Dr. M. Helliwell, Prof. D. J. Procter
School of Chemistry, University of Manchester
Oxford Road, M13 9PL (UK)
Fax : (+44)161-275-4939
E-mail: david.j.procter@manchester.ac.uk
The H2O cosolvent is essential for the reactivity observed
in our study. This observation is in line with Curranꢀs finding
that SmI2 is activated by H2O.[6] Flowers has since shown
that the reduction potential of SmI2 (À1.3 V) increases to a
maximum of À1.9 V on the addition of up to 500 equivalents
[b] Prof. H. Matsubara
Department of Chemistry, Graduate School of Science
Osaka Prefecture University, Sakai, Osaka 599-8531 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000632.
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FULL PAPER
Table 1. Reduction of cyclic 1,3-diesters with SmI2/H2O.
diesters in the presence of six-
membered lactones [Scheme 2,
Eq. (5)] although more reactive
six-membered lactones are re-
duced at comparative rates to
cyclic 1,3-diesters.[2]
Substrate
R1
R2
Product
R1
R2
Yield [%
The reduction of 1a with
SmI2/D2O gave [D,D]-2a (see
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Bn
Bn
2a
2b
2c
2d
2e
2 f
2g
2h
2 f
2d
2k
Bn
Bn
88[a]
81[a]
68[a]
78[a]
77[a]
94[a]
98[a]
72[a]
87[b]
69[b]
75[c]
À
À
À
N
À
(CH2)4
Bn
Scheme 3)
suggesting
that
H
H
H
H
Me
H
H
H
H
H
Me
H
H
H
H
Bn
anions are generated and pro-
tonated by H2O during a series
of electron transfer steps. A
possible mechanism for the
transformation is given in
Scheme 3. Activation of the
ester carbonyl by coordination
to SmII and electron transfer
generates radical anion 3 that is
then protonated. A second elec-
tron transfer generates carban-
CH2C6H4-4-OMe
CH2C6H4-4-Br
iBu
Bn
Ph
CH2C6H4-4-OMe
CH2C6H4-4-Br
iBu
Bn
Ph
iBu
=CHiPr
=CHC6H4-4-OMe
1j
1k
CH2C6H4-4-OMe
Et
À
À
CH2CH2
[a] Conditions: SmI2 (7 equiv), THF, H2O, 2-12 h. [b] Conditions: SmI2 (9 equiv), THF, H2O, 6-12 h. [c] Condi-
tions: SmI2 (10 equiv), THF, H2O, 1 h.
of H2O.[7] As in the reduction of lactones with SmI2/H2O,[2]
the cyclic nature of the substrate is essential for reaction.
Collapse of the cyclic ketal after carbonyl reduction appears
to account for the highly selective mono-reduction of cyclic
1,3-diesters.
ion 5 that is quenched by H2O. Hemiacetal 6 is in equilibri-
um with hydroxy aldehyde 7, which is reduced by a third
In some cases, cyclic 1,3-diesters bearing alkenes can also
be reduced smoothly to the corresponding 3-hydroxy acids
(Scheme 1). In the reduction of 1p, 1,5-hydrogen atom ab-
straction by the radical intermediate (cf. 3 in Scheme 3) re-
sults in partial isomerization of the alkene (2:1, terminal to
internal).
Scheme 1. Selective reductions of cyclic 1,3-diesters bearing alkenes with
SmI2/H2O.
Competition experiments have been carried out to illus-
trate the selectivity of SmI2/H2O for cyclic 1,3-diesters over
esters [Scheme 2, Eq. (1)] and acyclic 1,3-diesters [Scheme 2,
Eqs. (2), (3) and (4)]. Further competition experiments have
shown that, in some cases, SmI2/H2O can reduce cyclic 1,3-
Scheme 2. Selective reductions of cyclic 1,3-diesters with SmI2/H2O. [a]
1:1 mixture of substrates.
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D. J. Procter et al.
electron transfer from SmII to give a ketyl-radical anion 8. A
final electron transfer from SmII gives an organosamarium
that is protonated. The amount of SmI2 (approx. 7 equiv) re-
quired experimentally is consistent with a mechanism that
requires 4 electrons (4 equiv of SmI2). It is also important to
note that one equivalent of acetone is generated during the
reduction and it is likely that this is also reduced (a further
2 equiv of SmI2) (Scheme 3).
Scheme 4. Theoretical studies on the origin of the selectivity.
mediates that are prone to decarboxylation (see below). The
addition of radicals formed by the one electron reduction of
the ester carbonyl group to alkenes has little precedent in
organic synthesis.[2b,11]
Scheme 3. Mechanism of the mono-reduction of cyclic 1,3-diesters using
SmI2/H2O.
We propose that the observed selectivity has its origin in
the rate of the initial electron transfer to the carbonyl of
cyclic 1,3-diesters and that, as for six-membered lactones,[2]
anomeric stabilization of the radical anion intermediate 3 is
crucial for promoting the initial reduction step.[8] Calcula-
tions support this and suggest that electron transfer to the
ester carbonyl in cyclic 1,3-diesters is endothermic (relative
reaction energy ~50 kJmolÀ1) in all cases.[9] The relative re-
action energy of this step for substituted dimethyl malo-
nates, however, is calculated to be ~102–114 kJmolÀ1, signif-
icantly higher than those for cyclic systems (Scheme 4). The
second electron transfer is predicted to be more facile, sug-
gesting that the first reduction is rate-determining. Calcula-
tions also predict that the radical anions 3 derived from
cyclic 1,3-diesters adopt a half-chair conformation with the
radical in a pseudoaxial conformation, enjoying anomeric
stabilization.[8] Activation of the cyclic 1,3-diesters by coor-
dination to SmII and electrostatic stabilization of the product
radical-anion by coordination to SmIII[10] is likely to render
these reductions more favorable than the calculated, relative
reaction energies suggest.
The radical intermediates (cf. 3) can be exploited in radi-
cal cyclizations to form five-membered rings: cyclic 1,3-di-
esters 9–11 undergo efficient radical cyclization upon treat-
ment with SmI2/H2O to give cyclopentanones 15–17, respec-
tively, after esterification and oxidation (Scheme 5). The re-
duction of 10 with less SmI2 resulted in the isolation of cy-
clopentanone byproducts thus confirming that products 12–
14 result from cyclization of the first radical intermediate
(cf. 3) followed by reduction of the cyclopentanone inter-
Scheme 5. Preliminary studies on radical cyclization reactions of cyclic
1,3-diesters.
Unfortunately, the stereoselectivity observed in the cycli-
zations was only moderate (5:1 dr) even when a bulky
alkene was used (cf. substrate 11) (Scheme 5).[3] We pro-
posed that the diastereoselectivity of the radical cyclization
of cyclic 1,3-diesters could be improved by variation of the
ketal unit. To explore this idea, cyclization substrates 18–21
bearing different ketal units were prepared (Table 2). Treat-
ment of cyclic 1,3-diesters 18–21 with SmI2 in THF/H2O
gave cyclopentanol 22 in good yield. As the cyclopentanol
product 22 was obtained as a mixture of four diastereoiso-
mers, an esterification/oxidation sequence was again used to
prepare cyclopentanone 23 and thus simplify the diastereo-
isomeric mixture. Diastereoisomeric ratios were then ob-
1
tained by H NMR spectroscopy. We were pleased to find
that the nature of the ketal unit in the cyclic 1,3-diesters did
have an effect on the diastereoselectivity of the cyclization
with the acetophenone ketal giving the best stereoselectivity
(dr 7:1). The relative stereochemistry of 20, 22 (and there-
fore 23) was confirmed by X-ray crystallographic analysis.[12]
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Selective Reductions by Using SmI2 and H2O
FULL PAPER
Table 2. Effect of the ketal unit on the diastereoselectivity of radical cyc-
lizations of a cyclic 1,3-diesters.
Table 4. Cyclizations of cyclic 1,3-diesters mediated by SmI2/H2O.
Substrate
Cyclopentanol produc- Cyclopentanone
t[a,b]
substrate
R1
R2
Yield [%] 22
d.r. (of 23)
18
19
20
21
Me
Et
Ph
-(CH2)5-
Me
Et
Me
93
75
79
77
3:1
2:1
7:1
5:1
We next investigated the effect of temperature on the dia-
stereoselectivity of the SmI2-mediated cyclization and were
surprised to find that improved selectivity was observed at
higher temperature: cyclization of 20 at 508C gave 23 with
greater diastereoselectivity (dr 12:1) (Table 3). (The cycliza-
tion of the dimethylacetal substrate 18 at 508C gave 23 in
an enhanced diastereoisomeric ratio of 5:1 and an overall
yield of 70%).
Table 3. Effect of temperature on the diastereoselectivity of radical cycli-
zations of cyclic 1,3-diester.
[a] Reaction conditions: SmI2 (8 equiv) was added dropwise (over
30 min) to solution of the substrate (1 equiv) in THF and H2O
(1200 equiv) at 508C. [b] Diastereoisomeric ratios for cyclopentanols
refer to the ratio of the major diastereoisomer to the sum of the other
diastereoisomers.
a
T [8C]
Yield [%] 22
d.r. (of 23)
0
RT
50
81
78
89
3:1
7:1
12:1
Although it is possible that the cyclizations proceed by an
anionic path,[13] to our knowledge the addition of organosa-
mariums derived from carbonyls to alkenes is without prece-
dent. In addition, the presence of a large excess of H2O in
the reactions would appear to rule out an anionic reaction,
particular as it has been shown that anions are protonated
very quickly in H2O as the proton source coordinates to the
Sm center of the organosamarium intermediates and proto-
nation is intramolecular in nature.[14] We therefore suggest
that the cyclizations follow a radical pathway.
The preference for the formation of axial radicals in the
reduction[8] leads to possible radicals 45/46 and 47/48. In the
case of dimethyl acetals (R1 =Me), we believe both axial
radicals are accessible due to the similarity in energy be-
tween the two radicals (45 and 47) and the conformations of
the starting material that give rise to them. However, only
axial radical 45 can undergo cyclization through an electron-
ically favored anti transition structure[15] to give the major
product observed.[16] Axial radical 47 may undergo radical
interconversion[13b] to give an equatorial radical that then cy-
With optimized cyclization conditions in hand, we synthe-
sized a range of cyclic 1,3-diesters from malonic acid and
acetophenone, varying the substituent on the cyclic 1,3-di-
ester and on the alkene (20 and 24–30). In all cases, treat-
ment with SmI2/H2O in THF at 508C gave good yields of cy-
clopentanol product (72–90%, 22 and 31–37). Moderate dia-
stereoselectivity (8:1 dr to 3:1 dr) was also observed in the
ketone reduction step (Table 4). Again, an esterification/oxi-
dation sequence was used to simplify the diastereoisomeric
mixture and give cyclopentanones (60–86%, 23 and 38–44)
in moderate to excellent diastereoisomeric excess (3:1 to
33:1 dr) (Table 4). The relative stereochemistry of 40 was
determined by X-ray crystallographic analysis of a deriva-
tive.[12] The cyclization of substrates 29 and 30, bearing unac-
tivated, terminal alkenes, was also efficient although diaste-
reoselectivities were lower. The relative stereochemistry of
37 was confirmed by comparison to a related compound
whose structure was determined by X-ray crystallographic
analysis.[3]
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D. J. Procter et al.
clizes in a less selective fashion. Ring interconversion be-
tween 47 and 45 may also occur but this would be expected
to have a higher energy barrier than radical interconver-
sion.[13b] We therefore believe that the use of the acetophe-
none ketal (R1 =Ph) leads to improved diastereoselectivity
in the cyclizations by exerting greater conformational con-
trol over the substrates and the intermediate radical anions
and thus axial radical 46 is formed selectively (Scheme 6).
second alkene would result in a second radical cyclization
event. To evaluate the feasibility of such cyclization cascades
we prepared substrates 51-53. Pleasingly, treatment of bis-
alkene substrates 51 and 52 with SmI2/H2O gave the expect-
ed bicyclic products 54 and 55, respectively, in moderate
yield and with good diastereocontrol[19] (Scheme 8).
Scheme 8. Cyclization cascades of cyclic 1,3-diesters.
The relative stereochemistry of 54 was confirmed by X-
ray crystallographic analysis.[12] Bicyclic alcohol 54 was also
obtained from the cyclization of the acetophene-derived
ketal 53, thus confirming that ketoacids are also intermedi-
ates in the cyclizations of such substrates.
Scheme 6. Possible origin of selectivity in the cyclizations.
It is not clear why higher diastereoselectivities are ob-
tained at increased temperature. Although most radical cyc-
lizations are irreversible, cyclizations of stable radicals can
be reversible.[17] Although unlikely, it is therefore possible
that the cyclizations of these unusual radical anions may in
some cases be reversible with thermodynamic control lead-
ing to higher selectivity. However, this does not explain,
why the selectivity of cyclizations involving terminal alkenes
does not improve with increased temperature (see Table 4).
The absence of a group to stabilize the radical formed upon
cyclization make these substrates the most likely to undergo
reversible cyclizations. Another possibility is that the cyclo-
pentanol products formed in the reaction undergo epimeri-
zation by a retroaldol/aldol process upon heating. However,
this explanation is not consistent with the observation that
different acetals of otherwise identical substrates give differ-
ent diastereoisomeric ratios at higher temperatures. Studies
aimed at understanding this intriguing temperature effect
are continuing in our laboratory.
Conclusion
In summary, H2O activation of SmI2 allows the first reduc-
tion of cyclic 1,3-diesters using the reagent. The deconstruc-
tion of the cyclic system upon reduction ensures that no
over reduction occurs and 3-hydroxyacids are obtained in
good yield. The reagent system is selective for cyclic 1,3-di-
esters over acyclic 1,3-diesters, lactones, and esters. In addi-
tion to the selectivity of the reagent system, SmI2 is commer-
cially available, or convenient to prepare, easy to handle,
operates at ambient temperature, and does not require toxic
cosolvents or additives. Finally, the radicals formed by one
electron reduction of the ester carbonyl group can be ex-
ploited in highly diastereoselective intramolecular additions
to alkenes. The nature of the ketal unit and the reaction
temperature have a significant effect on the selectivity of
the reactions. Finally, cyclization cascades are possible when
two alkenes are present in the starting cyclic diester. The
cascades result in the formation of two rings and four ste-
reocenters with good stereocontrol.
We have also shown that radical anions generated from
cyclic-1,3-diesters can be exploited in transannular cycliza-
tions:[18] treatment of cycloheptene 49 with SmI2/H2O gave
bicyclic alcohol 50 as a single diastereoisomer in 55% yield
(Scheme 7).
Finally, the intermediacy of cyclopentanones in the reac-
tion sequence led us to speculate that the presence of a
Experimental Section
For general experimental procedures and experimental procedures and
characterisation data pertaining to Table 1 and Scheme 2 and 5, please
see our preliminary report.[3] Please see Supporting Information for addi-
tional experimental details, characterization data and 1H and 13C NMR
spectra for all new compounds, X-ray crystal structures for 20, 22, 50, 54
and a derivative of 40 and CCDC numbers.
General procedure A (GP A): SmI2-mediated reductions in THF/H2O
2-Cyclohexylmethyl-2-(hydroxymethyl)hept-6-enoic acid (2l): To a stirred
solution of 1l (30 mg, 0.098 mmol, 1 equiv) in THF (2.0 mL) and H2O
Scheme 7. Transannular cyclization of a cyclic 1,3-diester.
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Selective Reductions by Using SmI2 and H2O
FULL PAPER
(2.1 mL, 117 mmol, 1200 equiv) was added SmI2 (0.1m in THF, 8.0 mL,
0.800 mmol, 8 equiv) dropwise using a syringe pump over 30 min. After
decolorization of the reaction mixture, the reaction was opened to air
and saturated aqueous sodium chloride (15 mL) and tartaric acid (25 mg)
were added. The aqueous phase was extracted with ethyl acetate (3ꢂ
20 mL) and the combined organic phases dried (Na2SO4 or MgSO4) and
concentrated in vacuo. Purification by column chromatography on silica
gel, eluting with 50% CH2Cl2 in petroleum ether (40–608C) and 1%
acetic acid gave 2l (20 mg, 0.079 mmol, 81%) as a white solid. M.p. 88–
0.080 mmol, 82%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d =
0.91 (d, 6H, J=6.6 Hz, 2 ꢂ CH3CH), 1.21–1.35 (m, 2H, CH2), 1.35–1.45
(m, 2H, CH2), 1.49–1.65 (m, 3H, 3H from CH2), 1.66–1.78 (m, 2H, 1H
from CH2, 1H from CH2CH), 2.06 (q, 2H, J=7.0 Hz, CH2CH=CH2),
3.66 (d, 1H, J=11.3 Hz, 1H from CH2OH), 3.81 (d, 1H, J=11.3 Hz, 1H
from CH2OH), 4.95 (ddt, 1H, J=10.1, 1.8, 1.0 Hz, 1H from CH2 =CH),
5.00 (ddt, 1H, J=17.2, 1.8, 1.8 Hz, 1H from CH2=CH), 5.79 ppm (m, 1H,
J=17.2, 10.1, 6.8 Hz, CH2=CH); 13C NMR (100 MHz, CDCl3): d = 23.3
(CH2), 23.6 (CH2CH), 24.3 (CH3CH), 24.4 (CH3CH), 29.3 (CH2), 33.5
(CH2), 33.7 (CH2), 42.6 (CH2), 50.2 (Cq), 64.6 (CH2OH), 114.5 (CH2=
CH), 138.7 (CH2=CH), 183.1 ppm (C=O); IR (neat): nmax = 3376 (br,
OH), 3076, 2926, 2868, 2360, 1694 (C=O), 1640, 1462, 1387, 1367, 1238,
1037, 908 cmÀ1; MS (ES+): m/z: calcd for C13H25O3: 229.1798; found:
229.1798 [M+H]+.
1
908C; H NMR (400 MHz, CDCl3): d = 0.89–1.03 (m, 2H, 2H from Cy),
1.05–1.30 (m, 3H, 3H from Cy), 1.30–1.45 (m, 3H, 2H from CH2, 1H
from CH2CH), 1.49 (dd, 1H, J=14.4, 5.5 Hz, 1H from CH2CH), 1.54–
1.77 (m, 7H, 5H from Cy, 2H from CH2), 1.58 (dd, 1H, J=14.4, 6.6 Hz,
1H from CH2CH), 2.06 (q, 2H, J=7.1 Hz, CH2CH=CH2), 3.65 (d, 1H,
J=11.3 Hz, 1H from CH2OH), 3.81 (d, 1H, J=11.3 Hz, 1H from
CH2OH), 4.97 (d, 1H, J=10.2 Hz, 1H from CH2=CH), 5.02 (dd, 1H, J=
17.0, 1.4 Hz, 1H from CH2=CH), 5.78 ppm (ddt, 1H, J=17.0, 10.2,
6.7 Hz, CH2=CH); 13C NMR (100 MHz, CDCl3): d = 23.3 (CH2), 26.2
(CH2 from Cy), 26.4 (2 ꢂ CH2 from Cy), 33.6 (CH2), 33.8 (CH2CH), 34.1
(CH2), 34.2 (CH2 from Cy), 34.9 (CH2 from Cy), 41.3 (CH2CH), 50.0
(Cq), 64.7 (CH2OH), 114.9 (CH2=CH), 138.3 (CH2=CH), 183.1 ppm (C=
O); IR (neat): nmax = 3376 (br, OH), 2922, 2850, 1691 (C=O), 1640, 1448,
1257, 1235, 1217, 1034, 905, 827, 663 cmÀ1; MS (ES+): m/z (%): calcd for
C15H26O3Na: 277.1774; found: 277.1782 [M+Na]+.
2-Hydroxymethyl-2-isobutyl-6-phenyl-hept-5-enoic acid and 2-hydroxy-
methyl-2-isobutyl-6-phenyl-hept-6-enoic acid (2p): As for GP A, reaction
of 1p (75 mg, 0.227 mmol, 1 equiv) in THF (3.0 mL) and distilled water
(4.5 mL, 250 mmol, 1100 equiv) with SmI2 (0.1m in THF, 18.2 mL,
1.82 mmol, 8 equiv) after column chromatography on silica gel, eluting
with 60% ethyl acetate in petroleum ether (40–608C) gave 2p (2:1, ter-
minal alkene/internal alkene) (59 mg, 0.216 mmol, 95%) as a colorless
oil. Major regioisomer: 1H NMR (300 MHz, CDCl3): d = 0.76 (d, 3H,
J=6.6 Hz, CHCH3), 0.78 (d, 3H, J=6.6 Hz, CHCH3), 1.36 (m, 1H, CH),
1.41 (dd, 2H, J=6.0, 2.6 Hz, CCH2CH2), 1.45–1.78 (m, 4H, 2 ꢂ CH2),
2.32–2.55 (m, 2H, CH2 =CCH2), 3.49 (d, 1H, J=11.5 Hz, 1H from
CH2OH), 3.65 (d, 1H, J=11.5 Hz, 1H from CH2OH), 4.97 (d, 1H, J=
1.7 Hz, C=CH2) 5.21 (d, 1H, J=1.7 Hz, C=CH2), 7.06–7.37ppm (m, 5H,
5 ꢂ Ar-H); 13C NMR (75 MHz, CDCl3): d = 23.7 (CH), 24.2 (CHCH3),
24.3 (CHCH3), 29.7 (CH2), 33.0 (CH2), 35.6 (CH2 =CCH2), 42.4
2-Hydroxymethyl-2-isobutylhept-6-enoic acid (2m): As for GPA, reac-
tion of 1m (30 mg, 0.112 mmol, 1 equiv) in THF (2.0 mL) and H2O
(2.4 mL, 134 mmol, 1200 equiv) with SmI2 (0.1m in THF, 9.0 mL,
0.90 mmol, 8 equiv) after column chromatography on silica gel, eluting
with 30% ethyl acetate in petroleum ether (40–608C) gave 2m (16 mg,
0.074 mmol, 67%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d =
0.91 (d, 6H, J=6.6 Hz, 2 ꢂ CH3CH), 1.31–1.47 (m, 2H, CH2), 1.49–1.66
(m, 3H, 3H from CH2), 1.66–1.77 (m, 2H, 1H from CH2, 1H from
CH2CH), 2.06 (q, 2H, J=7.1 Hz, CH2CH=CH2), 3.65 (d, 1H, J=11.3 Hz,
1H from CH2OH), 3.82 (d, 1H, J=11.3 Hz, 1H from CH2OH), 4.97 (ddt,
1H, J=10.3, 1.8, 1.0 Hz, 1H from CH2=CH), 5.02 (ddt, 1H, J=17.2, 1.8,
1.8 Hz, 1H from CH2=CH), 5.79 ppm (ddt, 1H, J=17.2, 10.3, 6.6 Hz,
CH2=CH); 13C NMR (100 MHz, CDCl3): d = 23.2 (CH2), 23.6 (CH2CH),
24.3 (CH3CH), 24.4 (CH3CH), 33.4 (CH2), 34.1 (CH2), 42.6 (CH2CH),
50.1 (Cq), 64.7 (CH2OH), 114.9 (CH2=CH), 138.3 (CH2=CH), 183.1 ppm
(C=O); IR (neat): nmax = 3376 (br, OH), 3076, 2952, 2869, 2360, 1697
(C=O), 1640, 1460, 1388, 1367, 1234, 1038, 909 cmÀ1; MS (ES+): m/z:
calcd for C12H22O3Na: 237.1461; found: 237.1455 [M+Na]+.
(CCH2CH2), 50.1 (Cq), 64.7 (CH2OH), 112.7 (C=CH2), 126.1 (2
ArCH), 127.4 (ArCH), 128.3 (2
ArCH), 141.1 (Cq), 147.9 (ArCq),
ꢂ
ꢂ
182.8 ppm (C=O); minor regioisomer: 1H NMR (400 MHz, CDCl3): d =
0.85 (d, 6H, J=6.6 Hz, CHCH3), 1.45–1.84 (m, 5H, CH and 2 ꢂ CH2),
1.95 (d, 3H, J=1.3 Hz, CH=CCH3), 2.04–2.21 (m, 2H, CH2CH=C), 3.64
(d, 1H, J=11.6 Hz, 1H from CH2OH), 3.79 (d, 1H, J=11.6 Hz, 1H from
CH2OH), 5.66 (td, 1H, J=7.1, 1.4 Hz, CH=C), 7.01–7.35 ppm (m, 5H,
Ar-H); 13C NMR (100 MHz, CDCl3): d 15.8 (CH=CCH3), 23.5 (CH2),
23.7 (CHCH3), 24.4 (CHCH3), 24.4 (CH), 33.7 (CH2), 42.7 (CH2), 50.2
(Cq), 64.7 (CH2OH), 125.6 (2 ꢂ ArCH), 126.63 (ArCH), 127.4 (C=CH),
128.2 (2 ꢂ ArCH), 135.4 (Cq), 143.7 (Cq), 182.7 ppm (C=O); IR (evap.
film): nmax = 3409 (OH), 2954, 2927, 2868, 1698 (C=O), 1493, 1447, 1367,
1226, 1135, 1056, 1027, 919 cmÀ1; MS (ESÀ): m/z: calcd for C11H14O5Na:
289.1804; found: 289.1807 [MÀH+Na]+.
2-Cyclohexylmethyl-2-(hydroxymethyl)oct-7-enoic acid (2n): As for
GPA, reaction of 1n (30 mg, 0.093 mmol, 1 equiv) in THF (2.0 mL) and
H2O (2.0 mL, 112 mmol, 1200 equiv) with SmI2 (0.1m in THF, 7.5 mL,
0.75 mmol, 8 equiv) after column chromatography on silica gel, eluting
with 30% ethyl acetate in petroleum ether (40–608C) gave 2n (23 mg,
0.086 mmol, 92%) as a colorless oil. 1H NMR (400 MHz, CDCl3): d =
0.90–1.02 (m, 2H, 2H from Cy), 1.05–1.45 (m, 8H, 3H from Cy, 4H from
CH2, 1H from CH2CH), 1.49 (dd, 1H, J=14.4, 5.5 Hz, 1H from
CH2CH), 1.53–1.75 (m, 7H, 5H from Cy, 2H from CH2), 1.58 (dd, 1H,
J=14.4, 6.3 Hz, 1H from CH2CH), 2.07 (q, 2H, J=7.0 Hz, CH2CH=
CH2), 3.65 (d, 1H, J=11.3 Hz, 1H from CH2OH), 3.80 (d, 1H, J=
11.3 Hz, 1H from CH2OH), 4.95 (ddt, 1H, J=10.3, 1.8, 1.0 Hz, 1H from
CH2=CH), 5.01 (ddt, 1H, J=17.2, 1.8, 1.8 Hz, 1H from CH2=CH),
5.80 ppm (ddt, 1H, J=17.2, 10.3, 6.6 Hz, CH2=CH); 13C NMR (100 MHz,
CDCl3): d = 23.3 (CH2), 26.1 (CH2 from Cy), 26.3 (CH2 from Cy), 29.3
(CH2 from Cy), 29.7 (CH2), 33.5 (CH2), 33.8 (CH2CH, CH2), 34.2 (CH2
from Cy), 34.8 (CH2 from Cy), 41.2 (CH2CH), 50.0 (Cq), 64.7 (CH2OH),
General procedure B (GP B): SmI2-mediated cyclizations in THF/H2O
rac-
ACHTUNGTRENNUNG
boxylic acid (22): To
a
1 equiv) in THF (1.0 mL) and H2O (6.0 mL, 336 mmol, 1200 equiv) was
added SmI2 (0.1m in THF, 22.5 mL, 2.25 mmol, 8 equiv) dropwise using a
syringe pump over 30 min. After decolorization of the reaction mixture,
the reaction was opened to air and saturated aqueous sodium chloride
(15 mL) and tartaric acid (50 mg) were added. The aqueous phase was
extracted with ethyl acetate (3ꢂ20 mL) and the combined organic phases
dried (Na2SO4 or MgSO4) and concentrated in vacuo. Purification by
column chromatography on silica gel, eluting with 20% ethyl acetate in
petroleum ether (40–608C) gave 3-benzyl-1-cyclohexylmethyl-2-hydroxy-
cyclopentanecarboxylic acid (82 mg, 0.260 mmol, 93%) as a white solid.
The product was obtained as a mixture of four diastereoisomers of which
1
22 was the major diastereoisomer (3:1 (others)). M.p. 43–458C; H NMR
(400 MHz, CDCl3): d = 0.85–1.07 (m, 2H, 2H from CH2), 1.07–1.42 (m,
6H, 6H from CH2), 1.57–1.71 (m, 7H, 7H from CH2), 1.84–1.93 (m, 1H,
1H from CH2), 2.11–2.18 (m, 1H, ArCH2CH), 2.18–2.24 (m, 1H, 1H
from CH2), 2.50 (dd, 1H, J=13.4, 9.6 Hz, 1H from ArCH2), 3.03 (dd,
1H, J=13.4, 4.8 Hz, 1H from ArCH2), 3.84 (d, 1H, J=8.8 Hz, CHOH),
114.5 (CH2=CH), 138.7 (CH2=CH), 183.2 ppm (C=O); IR (neat): nmax
=
3376 (br, OH), 3076, 2920, 2850, 2360, 1694 (C=O), 1640, 1448, 1254,
1214, 1036, 988, 907, 732 cmÀ1; MS (ES+): m/z: calcd for C16H28O3Na:
291.1931291; found: 291.1932 [M+Na]+.
2-Hydroxymethyl-2-isobutyloct-7-enoic acid (2o): As for GPA, reaction
of 1o (31 mg, 0.111 mmol, 1 equiv) in THF (2.0 mL) and distilled water
(2.3 mL, 133 mmol, 1200 equiv) with SmI2 (0.1m in THF, 8.5 mL,
0.85 mmol, 8 equiv) after column chromatography on silica gel, eluting
with 30% ethyl acetate in petroleum ether (40–608C) gave 2o (18.3 mg,
7.17–7.24 (m, 3H, 3 ꢂ ArH), 7.26–7.33 ppm (m, 2H, 2 ꢂ ArH);
13C NMR (100 MHz, CDCl3): d = 25.0 (CH2), 25.2 (CH2), 25.3 (CH2),
25.4 (CH2), 27.7 (CH2), 32.4 (CH2), 33.3 (CH from Cy), 34.1 (CH2), 37.4
(HO2CCCH2), 38.8 (ArCH2), 44.9 (ArCH2CH), 53.6 (Cq), 81.6 (CHOH),
125.0 (ArCH), 127.3 (2
ꢂ
ArCH), 127.9 (2
ꢂ
ArCH), 139.7 (ArCq),
Chem. Eur. J. 2010, 16, 10240 – 10249
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10245

D. J. Procter et al.
182.8 ppm (C=O); IR (neat): nmax = 3395, 2920, 2849, 1693 (C=O), 1445,
1209, 1062, 748, 698 cmÀ1
MS (ES+): m/z: calcd for C20H28O3Na:
339.1931; found: 339.1934 [M+Na]+.
rac-(1R,2S,3S)-3-(4-Bromobenzyl)-1-cyclohexylmethyl-2-hydroxycyclo-
action was warmed to 508C prior to addition of SmI2 and that the tem-
perature was maintained until the reaction was quenched. Reaction of 29
(75 mg, 0.210 mmol, 1 equiv) in THF (2.0 mL) and H2O (4.2 mL,
233 mmol, 1100 equiv) with SmI2 (0.1m in THF, 16.8 mL, 1.68 mmol,
8 equiv) after column chromatography on silica gel, eluting with 10%
ethyl acetate in hexane gave 1-cyclohexylmethyl-2-hydroxy-3-methylcy-
clopentanecarboxylic acid (45 mg, 0.189 mmol, 90%) as a colorless oil.
The product was obtained as a mixture of four diastereoisomers which 36
was the major diastereoisomer (3:1 (others)). Characterization was un-
dertaken on the product of subsequent esterification and oxidation 43.
;
ACHTUNGTRENNUNG
pentanecarboxylic acid (31): As for GP B, with the exception that reac-
tion was warmed to 508C prior to addition of SmI2 and that the tempera-
ture was maintained until the reaction was quenched. Reaction of 24
(75 mg, 0.147 mmol, 1 equiv) in THF (2.0 mL) and H2O (2.9 mL,
161 mmol, 1100 equiv) with SmI2 (0.1m in THF, 11.7 mL, 1.17 mmol,
8 equiv) after column chromatography on silica gel, eluting with 10%
ethyl acetate in hexane gave 3-(4-bromobenzyl)-1-cyclohexylmethyl-2-hy-
droxy-cyclopentanecarboxylic acid (46 mg, 0.109 mmol, 74%) as a white
solid. The product was obtained as a mixture of four diastereoisomers of
which 31 was the major diastereoisomer (7:1 (others)). Characterization
was undertaken on the product of subsequent esterification and oxidation
38.
rac-ACTHNUGRTNEUNG(1R,2S,3S)-2-Hydroxy-1-isobutyl-3-methylcyclopentanecarboxylic
acid (37): As for general procedure B, with the exception that reaction
was warmed to 508C prior to addition of SmI2 and that the temperature
was maintained until the reaction was quenched. Reaction of 30 (60 mg,
0.189 mmol, 1 equiv) in THF (2.0 mL) and H2O (4.1 mL, 228 mmol,
1200 equiv) with SmI2 (0.1m in THF, 15.2 mL, 1.52 mmol, 8 equiv) after
column chromatography on silica gel, eluting with 10% ethyl acetate in
hexane gave 2-hydroxy-1-isobutyl-3-methylcyclopentanecarboxylic acid
(31 mg, 0.189 mmol, 82%) as a colorless oil. The product was obtained as
a mixture of four diastereoisomers which 37 was the major diastereoiso-
mer (3:1 (others)). Characterization was undertaken on the product of
subsequent esterification and oxidation 44.
rac-ACHTUNGTRENNUNG(1R,2S,3S)-3-Benzyl-2-hydroxy-1-isobutylcyclopentanecarboxylic acid
(32): As for general procedure B, with the exception that reaction was
warmed to 508C prior to addition of SmI2 and that the temperature was
maintained until the reaction was quenched. Reaction of 25 (76 mg,
0.243 mmol, 1 equiv) in THF (2.0 mL) and H2O (4.9 mL, 272 mmol,
1100 equiv) with SmI2 (0.1m in THF, 19.4 mL, 1.94 mmol, 8 equiv) after
column chromatography on silica gel, eluting with 10% ethyl acetate in
hexane gave 3-benzyl-2-hydroxy-1-isobutylcyclopentanecarboxylic acid
(43 mg, 0.202 mmol, 83%) as a colorless oil. The product was obtained as
a mixture of four diastereoisomers of which 32 was the major diastereo-
isomer (6:1 (others)). Characterization was undertaken on the product of
subsequent esterification and oxidation 39.
General Procedure C: Esterification-oxidation sequence to form keto-
esters
rac-ACTHNUGRTNEUNG(1R,3S)-3-Benzyl-1-cyclohexylmethyl-2-oxocyclopentanecarboxylic
acid methyl ester (23): To a stirred solution of the four diastereoisomers
of 3-benzyl-1-cyclohexylmethyl-2-hydroxycyclopentanecarboxylic acid
(33 mg, 0.104 mmol, 1 equiv) in methanol (4.0 mL) and toluene (1.0 mL),
was added dropwise trimethylsilyl diazomethane (2m in hexane,
0.115 mL, 0.229 mmol, 2.2 equiv) and the reaction stirred for 1 h. The sol-
vent was removed in vacuo and the crude product redissolved in CH2Cl2
(5.0 mL). Dess–Martin periodinane (65 mg, 0.155 mmol, 1.6 equiv) was
subsequently added, and the reaction stirred for 1.5 h prior to quenching
with water (15 mL). The aqueous phase was extracted with CH2Cl2 (3ꢂ
10 mL), the combined organic phases dried (MgSO4) and concentrated in
vacuo. Purification by column chromatography on silica gel, eluting with
5% ethyl acetate in hexane gave 3-benzyl-1-cyclohexylmethyl-2-oxo-cy-
clopentanecarboxylic acid methyl ester (30 mg, 0.092 mmol, 88%) as a
colorless oil and as an 12:1 mixture of diastereoisomers of which 23 was
rac-(1R,2S,3S)-3-(4-Bromobenzyl)-2-hydroxy-1-isobutylcyclopentanecar-
boxylic acid (33): As for general procedure B, with the exception that re-
action was warmed to 508C prior to addition of SmI2 and that the tem-
perature was maintained until the reaction was quenched. Reaction of 26
(62 mg, 0.130 mmol, 1 equiv) in THF (2.0 mL) and H2O (2.9 mL,
158 mmol, 1200 equiv) with SmI2 (0.1m in THF, 10.5 mL, 1.05 mmol,
8 equiv) after column chromatography on silica gel, eluting with 10%
ethyl acetate in hexane gave 3-(4-bromobenzyl)-2-hydroxy-1-isobutyl-cy-
clopentanecarboxylic acid (37 mg, 0.104 mmol, 80%) as a colorless oil.
The product was obtained as a mixture of four diastereoisomers of which
33 was the major diastereoisomer (4:1 (others)). Characterization was
undertaken on the product of subsequent esterification and oxidation 40.
the major. 1H NMR (400 MHz, CDCl3): d
= 0.97–1.10 (m, 2H, CH2
rac-(1R,2S,3S)-2-Hydroxy-1-isobutyl-3-naphthalen-1-ylmethylcyclopenta-
necarboxylic acid (34): As for general procedure B, with the exception
that reaction was warmed to 508C prior to addition of SmI2 and that the
temperature was maintained until the reaction was quenched. Reaction
of 27 (55 mg, 0.124 mmol, 1 equiv) in THF (2.0 mL) and H2O (2.7 mL,
272 mmol, 1200 equiv) with SmI2 (0.1m in THF, 10 mL, 1.0 mmol,
8 equiv) after column chromatography on silica gel, eluting with 10%
ethyl acetate in hexane gave 2-hydroxy-1-isobutyl-3-naphthalen-1-ylme-
thylcyclopentanecarboxylic acid (33 mg, 0.202 mmol, 82%) as a colorless
oil. The product was obtained as a mixture of four diastereoisomers of
which 34 was the major diastereoisomer (7:1 (others)). Characterization
was undertaken on the product of subsequent esterification and oxidation
41.
from Cy), 1.14–1.36 (m, 2H, CH2 from Cy), 1.35–1.49 (m, 1H, CH from
Cy), 1.56 (dd, 1H, J=14.1, 6.6 Hz, 1H from CH2Cy), 1.61–1.88 (m, 8H,
6H from Cy, 1H from CHCH2CH2, 1H from CHCH2CH2), 2.09–2.17 (m,
1H, 1H from CHCH2CH2), 2.20 (dd, 1H, J=14.1, 6.6 Hz, 1H from
CH2Cy), 2.51–2.66 (m, 1H, CHCH2Ph), 2.67–2.75 (m, 2H, 1H from
CH2Ph, 1H from CHCH2CH2), 3.27 (dd, 1H, J=13.5, 3.9 Hz, 1H from
CH2Ph), 3.74 (s, 3H, OCH3), 7.27 ppm (m, 5H, 5 ꢂ Ar-H); 13C NMR
(100 MHz, CDCl3): d = 26.1 (CH2 from Cy), 26.2 (2 ꢂ CH2 from Cy),
26.4 (CH2 from Cy), 30.9 (CHCH2CH2), 33.5 (CH2 from Cy), 34.1 (CH2
from Cy), 34.8 (CH from Cy), 36.3 (CH2Ar), 42.5 (CCH2), 50.9
(CHCH2Ar), 52.5 (OCH3), 61.2 (Cq), 126.2 (ArCH), 128.3 (2 ꢂ ArCH),
129.0 (2 ꢂ ArCH), 139.4 (ArCq), 170.9 (COOCH3), 214.9 ppm (C=O);
IR (evap. film): nmax = 2923, 2850, 2362, 1747 (C=O), 1721 (C=O), 1450,
1210, 912, 699 cmÀ1; MS (ES+): m/z: calcd for C21H28O3Na: 351.1917;
found: 351.1931 [M+Na]+.
rac-(1R,2S,3S)-3-(5-Bromo-2-methoxybenzyl)-2-hydroxy-1-isobutylcyclo-
pentanecarboxylic acid (35): As for general procedure B, with the excep-
tion that reaction was warmed to 508C prior to addition of SmI2 and that
the temperature was maintained until the reaction was quenched. Reac-
tion of 28 (33 mg, 0.070 mmol, 1 equiv) in THF (2.0 mL) and H2O
(1.4 mL, 79.2 mmol, 1200 equiv) with SmI2 (0.1m in THF, 5.3 mL,
0.53 mmol, 8 equiv) after column chromatography on silica gel, eluting
with 10% ethyl acetate in hexane gave 3-(5-bromo-2-methoxybenzyl)-2-
hydroxy-1-isobutylcyclopentanecarboxylic acid (18.2 mg, 0.202 mmol,
72%) as a colorless oil. The product was obtained as a mixture of four
diastereoisomers of which 35 was the major diastereoisomer (8:1
(others)). Characterization was undertaken on the product of subsequent
esterification and oxidation 42.
rac-(1R,3S)-3-(4-Bromobenzyl)-1-cyclohexylmethyl-2-oxo-cyclopentane
carboxylic acid methyl ester (38): As for general procedure C, the four
diastereoisomers of 3-(4-bromobenzyl)-1-cyclohexylmethyl-2-hydroxycy-
clopentanecarboxylic acid (58 mg, 0.109 mmol, 1 equiv) in methanol
(1.0 mL) and toluene (0.25 mL), were treated with trimethylsilyl diazo-
methane (2m in hexane, 0.436 mL, 0.872 mmol, 8 equiv) added dropwise
over 4 h. When the reaction was complete, the solvent was removed in
vacuo and the crude product redissolved in CH2Cl2 (2.0 mL). Treatment
with the Dess–Martin periodinane (96 mg, 0.230 mmol, 2.1 equiv) and pu-
rification by column chromatography on silica gel, eluting with 3% ethyl
acetate in hexane, gave 3-(4-bromobenzyl)-1-cyclohexylmethyl-2-oxo-cy-
clopentane carboxylic acid methyl ester (37 mg, 0.089 mmol, 82%) as a
colorless oil and as a 33:1 mixture of diastereoisomers of which 38 was
rac-
ACHTUNGTRENNUNG(1R,2S,3S)-1-Cyclohexylmethyl-2-hydroxy-3-methylcyclopentanecar-
boxylic acid (36): As for general procedure B, with the exception that re-
10246
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 10240 – 10249

Selective Reductions by Using SmI2 and H2O
FULL PAPER
the major. 1H NMR (400 MHz, CDCl3): d
=
0.83–0.98 (m, 2H, CH2
131.4 (2 ꢂ ArCH), 138.2 (ArCq), 170.6 (COOCH3), 214.5 ppm (C=O);
IR (evap. film): nmax = 2925, 2955, 1750, 1749 (C=O), 1723 (C=O), 1487,
from Cy), 1.06–1.21 (m, 2H, CH2 from Cy), 1.21–1.34 (m, 1H, CH), 1.43
(dd, 1H, J=14.2, 6.4 Hz, 1H from CH2Cy), 1.51–1.71 (m, 8H, 6H from
Cy, 1H from CHCH2CH2, 1H from CHCH2CH2), 1.95–2.04 (m, 1H, 1H
from CHCH2CH2), 2.08 (dd, 1H, J=14.2, 6.4 Hz, CH2 from Cy), 2.42–
2.51 (m, 1H, CHCH2Ar), 2.53–2.63 (m, 2H, 1H from CH2Ar, 1H from
CHCH2CH2), 3.07 (dd, 1H, J=13.7, 4.2 Hz, 1H from CH2Ar), 3.62 (s,
3H, OCH3), 7.03 (d, 2H, J=8.3 Hz, 2 ꢂ ArCH), 7.38 ppm (d, 2H, J=
8.3 Hz, 2 ꢂ ArCH); 13C NMR (100 MHz, CDCl3): d = 26.1 (CH2), 26.3
(brs, 3 ꢂ CH2), 31.0 (CHCH2CH2), 33.5 (CH2 from Cy), 34.2 (CH2 from
Cy), 34.9 (CH from Cy), 35.7 (CH2Ar), 42.6 (CH2Cy), 50.6 (CHCH2Ar),
52.5 (OCH3), 61.2 (Cq), 120.1 (ArCq), 130.9 (2 ꢂ ArCH), 131.4 (2 ꢂ
ArCH), 138.3 (ArCq), 170.9 (COOH), 214.7 ppm (C=O); IR (neat):
nmax = 2921, 2850, 1748 (C=O), 1720 (C=O), 1487, 1447, 1207, 1157,
1488, 1218, 1162, 1011, 903, 704 cmÀ1
; MS (ES+): m/z: calcd for
C18H23O3BrNa: 391.0692; found: 391.0702 [M+Na]+.
rac-(1R,3S)-1-Isobutyl-3-naphthalen-1-ylmethyl-2-oxocyclopentanecar-
boxylic acid methyl ester (41): As for general procedure C, the four dia-
stereoisomers of 2-hydroxy-1-isobutyl-3-naphthalen-1-ylmethyl-cyclopen-
tanecarboxylic acid (33 mg, 0.101 mmol, 1 equiv) in methanol (4.0 mL)
and toluene (1.0 mL), were treated with trimethylsilyl diazomethane (2m
in hexane, 0.110 mL, 0.223 mmol, 2.2 equiv) dropwise over 1 h. When the
reaction was complete, the solvent was removed in vacuo and the crude
product redissolved in CH2Cl2 (5.0 mL). Treatment with the Dess–Martin
periodinane (61.2 mg, 0.146 mmol, 1.55 equiv) and purification by column
chromatography on silica gel, eluting with 5% ethyl acetate in hexane
1071, 1010, 732 cmÀ1
429.1036; found: 429.1034 [M+Na]+.
; MS (ES+): m/z: calcd for C21H27O3BrNa:
gave
1-isobutyl-3-naphthalen-1-ylmethyl-2-oxo-cyclopentanecarboxylic
acid methyl ester (25 mg, 0.073 mmol, 81%) as a yellow oil and as a 7:1
mixture of diastereoisomers of which 41 was the major. 1H NMR
(400 MHz, CDCl3): d = 0.87 (d, 3H, J=4.8 Hz, CHCH3), 0.88 (d, 3H,
J=4.8 Hz, CHCH3), 1.45 (dd, 1H, J=14.1, 6.8 Hz, CH2CHCH3), 1.60–
1.79 (m, 3H, CHCH3, 1H from CHCH2CH2, 1H from CHCH2CH2),
1.88–2.02 (m, 1H, CHCH2CH2), 2.17 (dd, 1H, J=14.1, 6.8 Hz,
CH2CHCH3), 2.58–2.71 (m, 2H, 1H from CHCH2CH2, 1H from
CHCH2CH2), 2.78–2.85 (m, 1H, CH2Ar), 3.71 (s, 3H, OCH3), 3.84 (dd,
1H, J=14.1, 3.7 Hz, CH2Ar), 7.29–7.33 (m, 1H, ArH), 7.37–7.42 (m, 1H,
ArH), 7.47–7.56 (m, 2H, ArH), 7.75 (d, 1H, J=8.1 Hz, ArH), 7.87 (d,
1H, J=7.6 Hz, ArH), 8.06 ppm (d, 1H, J=8.3 Hz, ArH); 13C NMR
rac-(1R,3S)-3-Benzyl-1-isobutyl-2-oxo-cyclopentanecarboxylic
G
acid
methyl ester (39): As for general procedure C, the four diastereoisomers
of 3-benzyl-2-hydroxy-1-isobutylcyclopentanecarboxylic acid (43 mg,
0.158 mmol, 1 equiv) in methanol (1.0 mL) and toluene (0.25 mL), were
treated with trimethylsilyl diazomethane (2m in hexane, 0.630 mL,
1.26 mmol, 8 equiv) added dropwise over 4 h. When the reaction was
complete, the solvent was removed in vacuo and the crude product redis-
solved in CH2Cl2 (2.0 mL). Treatment with the Dess–Martin periodinane
(120 mg, 0.255 mmol, 1.8 equiv) and purification by column chromatogra-
phy on silica gel, eluting with 3% ethyl acetate in hexane gave3-benzyl-
1-isobutyl-2-oxo-cyclopentanecarboxylic acid methyl ester (35 mg,
0.137 mmol, 81%) as a colorless oil and as a 7:1 mixture of diastereoiso-
mers of which 39 was the major. 1H NMR (400 MHz, CDCl3): d = 0.83
(d, 3H, J=6.6 Hz, CHCH3), 0.86 (d, 3H, J=6.6 Hz, CHCH3), 1.40 (dd,
1H, J=14.0, 6.9 Hz, 1H from CH2CHCH3), 1.55–1.74 (m, 3H, CHCH3,
1H from CHCH2CH2, 1H from CHCH2CH2)), 1.95–2.04 (m, 1H, 1H
from CHCH2CH2), 2.12 (dd, 1H, J=14.0, 6.6 Hz, 1H from CH2CHCH3),
2.42–2.52 (m, 1H, CHCH2Ar), 2.54–2.62 (m, 2H, 1H from CHCH2CH2,
1H from CH2Ar), 3.12 (dd, 1H, J=13.6, 4.0 Hz, 1H from CH2Ar), 3.60
(s, 3H, OCH3), 7.09–7.14 (m, 2H, 2 ꢂ ArCH), 7.17–7.21 (m, 1H, ArCH),
7.22–7.28 ppm (m, 2H, 2 ꢂ ArCH); 13C NMR (100 MHz, CDCl3): d =
(100 MHz, CDCl3): d = 23.0 (CHCH3), 23.6 (CHCH3), 25.5 (CH
27.3 (CHCH2CH2), 31.0 (CHCH2CH2), 33.8 (CH2Ar), 43.9 (CH2CH-
(CH3)2), 50.2 (CHCH2Ar), 52.5 (OCH3), 61.4 (Cq), 123.5 (ArCH), 125.4
ACHTUNGTRENNUNG(CH3)2),
AHCTUNGTRENNUNG
(ArCH), 125.6 (ArCH), 126.0 (ArCH), 126.8 (ArCH), 127.1 (ArCH),
128.8 (ArCH), 131.6 (ArCq), 133.9 (ArCq), 135.7 (ArCq), 171.0
(COOCH3), 214.9 ppm (C=O); IR (evap. film): nmax = 2954, 2862, 1747
(C=O), 1717 (C=O), 1446, 1217, 1161, 1013, 776 cmÀ1; MS (ES+): m/z:
calcd for C22H26O3Na: 361.1774; found: 361.1769 [M+Na]+.
rac-(1R,3S)-3-(5-Bromo-2-methoxybenzyl)-1-isobutyl-2-oxocyclopentane-
carboxylic acid methyl ester (42): As for general procedure C, the four
diastereoisomers of 3-(5-bromo-2-methoxybenzyl)-2-hydroxy-1-isobutyl-
cyclopentanecarboxylic acid (43 mg, 0.112 mmol, 1 equiv) in methanol
(4.0 mL) and toluene (1.0 mL), were treated with trimethylsilyl diazome-
thane (2m in hexane, 0.120 mL, 0.246 mmol, 2.2 equiv) dropwise over 1 h.
When the reaction was complete, the solvent was removed in vacuo and
the crude product redissolved in CH2Cl2 (5.0 mL). Treatment with the
Dess–Martin periodinane (72 mg, 0.171 mmol, 1.55 equiv) and purifica-
tion by column chromatography on silica gel, eluting with 5% ethyl ace-
tate in hexane gave 3-(5-bromo-2-methoxybenzyl)-1-isobutyl-2-oxocyclo-
pentanecarboxylic acid methyl ester (30 mg, 0.075 mmol, 70%) as a col-
orless oil and as a 5:1 mixture of diastereoisomers of which 42 was the
23.1 (CHCH3), 23.6 (CHCH3), 25.6 (CH
ACHTUNGTRENNUNG
(CHCH2CH2), 36.3 (CH2Ar), 44.0 (CH2CHACHTUNGTRENNNUG
52.5 (OCH3), 61.6 (Cq), 126.3 (ArCH), 128.4 (2 ꢂ ArCH), 129.0 (2 ꢂ
ArCH), 139.4 (ArCq), 170.7 (COOCH3), 214.8 ppm (C=O); IR (neat):
nmax = 2954, 2871, 2361, 2343, 1748 (C=O), 1721 (C=O), 1453,1216, 1161,
699 cmÀ1
; MS (ES+): m/z: calcd for C18H24O3Na: 311.1618; found:
311.1629 [M+Na]+.
rac-(1R,3S)-3-(4-Bromobenzyl)-1-isobutyl-2-oxo-cyclopentane carboxylic
acid methyl ester (40): As for general procedure C, the four diastereoiso-
mers of 3-(4-bromobenzyl)-2-hydroxy-1-isobutylcyclopentanecarboxylic
acid (78 mg, 0.22 mmol, 1 equiv) in methanol (4.0 mL) and toluene
(1.0 mL), were treated with trimethylsilyl diazomethane (2m in hexane,
0.240 mL, 0.485 mmol, 2.2 equiv) dropwise over 1 h. When the reaction
was complete, the solvent was removed in vacuo and the crude product
redissolved in CH2Cl2 (5.0 mL). Treatment with the Dess–Martin periodi-
nane (136 mg, 0.320 mmol, 1.55 equiv) and purification by column chro-
matography on silica gel, eluting with 5% ethyl acetate in hexane gave 3-
(4-bromobenzyl)-1-isobutyl-2-oxo-cyclopentanecarboxylic acid methyl
ester (31 mg, 0.084 mmol, 60%) as a yellow oil and as an 25:1 mixture of
diastereoisomers of which 40 was the major. 1H NMR (400 MHz,
CDCl3): d = 0.85 (d, 3H, J=6.6 Hz, CHCH3), 0.87 (d, 3H, J=6.6 Hz,
CHCH3), 1.41 (dd, 1H, J=14.1, 6.8 Hz, 1H from CH2CHCH3), 1.56–1.74
(m, 3H, CHCH3, 1H from CHCH2CH2, 1H from CHCH2CH2), 1.94–2.06
(m, 1H, 1H from CHCH2CH2), 2.13 (dd, 1H, J=14.1, 6.6 Hz,
CH2CHCH3), 2.39–2.52 (m, 1H, CHCH2CH2), 2.55–2.63 (m, 2H, 1H
from CHCH2CH2, 1H from CH2Ar), 3.06 (dd, 1H, J=13.7, 4.2 Hz, 1H
from CH2Ar), 3.61 (s, 3H, OCH3), 7.01 (d, 2H, J=8.3 Hz, 2 ꢂ ArH),
7.39 ppm (d, 2H, J=8.3 Hz, 2 ꢂ ArH); 13C NMR (100 MHz, CDCl3):
major. 1H NMR (400 MHz, CDCl3):
d = 0.78 (d, 3H, J=6.8 Hz,
CHCH3), 0.80 (d, 3H, J=6.8 Hz, CHCH3), 1.41 (dd, 1H, J=14.1, 6.8 Hz,
CH2CHCH3), 1.47–1.71 (m, 3H, 1H from CHCH3, 1H from CHCH2CH2,
1H from CHCH2CH2), 1.89–2.03 (m, 1H, CHCH2CH2), 2.13 (dd, 1H, J=
14.1, 6.8 Hz, CH2CHCH3), 2.39–2.51 (m, 2H, 1H from CHCH2CH2, 1H
from CH2Ar), 2.51–2.72 (m, 1H, CHCH2CH2), 3.15–3.23 (m, 1H,
CH2Ar), 3.68 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 6.68–6.73 (m, 1H,
ArH), 7.18–7.22 (m, 1H, ArH), 7.25–7.32 ppm (m, 1H, ArH); 13C NMR
(100 MHz, CDCl3): d = 23.0 (CHCH3), 23.6 (CHCH3), 25.5 (CH
ACHTUNGTRENNUNG(CH3)2),
26.6 (CH2CH2CH2), 30.6 (CHCH2CH2), 31.0 (CH2CH2CH2), 44.0
(CH2CHACHTUNGRTNEUNG(CH3)2), 49.1 (CHCH2Ar), 52.5 (OCH3), 55.4 (OCH3Ar), 61.3
(Cq), 111.8 (ArCH), 112.4 (ArCq), 130.1 (ArCq), 130.2 (ArCH), 133.1
(ArCH), 156.6 (ArCq), 170.9 (COOCH3), 214.8 ppm (C=O); IR (evap.
film): nmax
= 2954, 1747 (C=O), 1723 (C=O), 1489, 1247, 1029, 803,
623 cmÀ1; MS (ES+): m/z: calcd for C19H25O4BrNa: 419.0828; found:
419.0830 [M+Na]+.
rac-ACTHNUGRTNEUNG(1R,3R)-1-Cyclohexylmethyl-3-methyl-2-oxocyclopentane carboxylic
d = 23.0 (CHCH3), 23.6 (CHCH3), 25.5 (CH
31.0 (CHCH2CH2), 35.6 (CHCH2Ar), 43.9 (CH2CH
(CHCH2Ar), 52.5 (OCH3), 61.5 (Cq), 120.1 (ArCq), 130.8 (2 ꢂ ArCH),
G
acid methyl ester (43): As for general procedure C, the four diastereoiso-
mers of 1-cyclohexylmethyl-2-hydroxy-3-methyl-cyclopentanecarboxylic
acid (40 mg, 0.170 mmol, 1 equiv) in methanol (1.0 mL) and toluene
AHCTUNGTRENNUNG
Chem. Eur. J. 2010, 16, 10240 – 10249
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10247

D. J. Procter et al.
(0.25 mL), were treated with trimethylsilyl diazomethane (2m in hexane,
0.680 mL, 1.36 mmol, 8 equiv) added dropwise over 4 h. When the reac-
tion was complete, the solvent was removed in vacuo and the crude prod-
uct redissolved in CH2Cl2 (2.0 mL). Treatment with the Dess–Martin pe-
riodinane (107 mg, 0.255 mmol, 1.5 equiv) and purification by column
chromatography on silica gel, eluting with 3% ethyl acetate in hexane
gave 1-cyclohexylmethyl-3-methyl-2-oxo-cyclopentanecarboxylic acid
methyl ester (35 mg, 0.137 mmol, 81%) as a colorless oil and as a 3:1
mixture of diastereoisomers of which 43 was the major. 1H NMR
(400 MHz, CDCl3): d = 0.82–0.98 (m, 2H, CH2 from Cy), 1.04–1.22 (m,
5H, CH2 from Cy, CHCH3), 1.27–1.35 (m, 1H, CH from Cy), 1.42 (dd,
1H, J=14.1, 6.6 Hz, 1H from CH2Cy), 1.52–1.69 (m, 7H, 6H from Cy,
1H from CHCH2CH2), 1.75 (ddd, 1H, J=13.0, 11.6, 6.2 Hz, 1H from
CHCH2CH2), 2.06 (dd, 1H, J=14.1, 6.6 Hz, 1H from CH2Cy), 2.13–2.28
(m, 2H, CHCH3, 1H from CHCH2CH2), 2.60 (ddd, 1H, J=13.0, 6.4,
2.0 Hz, 1H from CHCH2CH2), 3.69 ppm (s, 3H, OCH3); 13C NMR
(100 MHz, CDCl3): d = 15.1 (CHCH3), 26.1 (CH2 from Cy), 26.2–26.3
(brs, 2 ꢂ CH2 from Cy), 29.1 (CHCH2CH2), 31.1 (CHCH2CH2), 33.5
(CH2 from Cy), 34.1 (CH2 from Cy), 34.8 (CH from Cy), 42.5 (CH2Cy),
43.7 (CHCH3), 52.4 (OCH3), 60.5 (Cq), 171.5 (COOCH3), 216.6 ppm (C=
O); IR (neat): nmax = 2923, 2851, 2358, 1748 (C=O), 1722 (C=O), 1488,
General Procedure D: SmI2-mediated cyclization cascades in THF/H2O
rac-(1R,3aS,6R,6aS)-1,6-Dibenzyl-6a-hydroxyoctahydropentalene-3a-car-
boxylic acid (54): To
a stirred solution of 51 (100 mg, 0.250 mmol,
1 equiv) in THF (1.0 mL) and H2O (5.4 mL, 297 mmol, 1200 equiv) was
added SmI2 (0.1m in THF, 19.8 mL, 1.98 mmol, 8 equiv) dropwise using a
syringe pump over 30 min. After decolorization of the reaction mixture,
the flask was opened to air and saturated aqueous sodium chloride
(15 mL) was added. The aqueous phase was extracted with ethyl acetate
(3ꢂ15 mL) and the combined organic phases dried (Na2SO4) and concen-
trated in vacuo. Purification by column chromatography on silica gel,
eluting with a gradient of 20% ethyl acetate in petroleum ether (40–
608C) gave 54 (60 mg, 0.173 mmol, 69%) as a white solid. M.p. 132–
1348C (ethyl acetate); 1H NMR (400 MHz, CDCl3): d = 1.15–1.40 (m,
2H, 2H from CH2), 1.54 (dd, 1H, J=13.1, 6.3 Hz, 1H from CH2), 1.58–
1.72 (m, 2H, 2H from CH2), 1.72–1.81 (m, 1H, 1H from CH2), 2.04–2.23
(m, 3H, 1H from CH2, 2 ꢂ CH), 2.48 (ddd, 1H, J=13.1, 6.1, 1.5 Hz, 1H
from CH2), 2.54–2.64 (m, 2H, 2H from PhCH2), 3.14 (dd, 1H, J=13.6,
2.5 Hz, 1H from PhCH2), 3.34 (dd, 1H, J=12.7, 3.2 Hz, 1H from
PhCH2), 7.20–7.26 (m, 6H, 6 ꢂ ArH), 7.28–7.36 ppm (m, 4H, 4 ꢂ ArH);
13C NMR (100 MHz, CDCl3): d = 27.6 (CH2), 32.0 (CH2), 34.8 (CH2),
35.7 (PhCH2), 35.9 (CH2), 36.5 (PhCH2), 48.2 (CH), 55.4 (CH), 64.4 (Cq),
92.7 (Cq), 125.9 (ArCH), 126.0 (ArCH), 128.4 (2 ꢂ ArCH), 128.4 (2 ꢂ
1247, 1207, 1130 1011, 925, 767 cmÀ1
C15H24O3Na: 275.1611; found: 275.1618 [M+Na]+.
; MS (ES+): m/z: calcd for
ArCH), 128.8 (2
ꢂ ArCH), 128.9 (2 ꢂ
ArCH), 141.3 (ArCq), 142.1
(ArCq), 181.9 ppm (C=O); IR (evap. film): nmax = 2950, 1703, 1682, 1494,
1454, 1276, 698 cmÀ1; MS (ES+): m/z: calcd for C23H25O3: 349.1804;
found: 349.1797 [MÀH]+.
rac-(1R,3S)-1-Isobutyl-3-methyl-2-oxocyclopentanecarboxylic
N
acid
methyl ester (44): As for general procedure C, the four diastereoisomers
of 1-cyclohexylmethyl-2-hydroxy-3-methylcyclopentanecarboxylic acid
(40 mg, 0.170 mmol, 1 equiv) in methanol (1.0 mL) and toluene
(0.25 mL), were treated with trimethylsilyl diazomethane (2m in hexane,
0.680 mL, 1.36 mmol, 8 equiv) added dropwise over 4 h. When the reac-
tion was complete, the solvent was removed in vacuo and the crude prod-
uct redissolved in CH2Cl2 (2.0 mL). Treatment with the Dess–Martin pe-
riodinane (107 mg, 0.255 mmol, 1.5 equiv) and purification by column
chromatography on silica gel, eluting with 3% ethyl acetate in hexane
gave 1-cyclohexylmethyl-3-methyl-2-oxocyclopentanecarboxylic acid
methyl ester (35 mg, 0.137 mmol, 81%) as a colorless oil and as a 3:1
mixture of diastereoisomers of which 44 was the major. 1H NMR
(400 MHz, CDCl3): d = 0.84 (d, 3H, J=6.8 Hz, CHCH3), 0.89 (d, 3H,
J=6.8 Hz, CHCH3), 1.12 (d, 3H, J=7.1 Hz, CH3), 1.42 (dd, 1H, J=14.1,
6.6 Hz, 1H from CH2CHCH3), 1.46–1.51 (m, 1H, 1H from CH2), 1.60–
1.74 (m, 1H, CHCH3), 1.95 (dd, 1H, J=14.1, 6.8 Hz, 1H from
CH2CHCH3), 1.96–2.02 (m, 1H, 1H from CH2), 2.16–2.25 (m, 1H, 1H
from CH2), 2.30–2.40 (m, 1H, CHCO), 2.53 (ddd, 1H, J=13.4, 9.3,
7.1 Hz, CH2), 3.69 ppm (s, 3H, OCH3); 13C (100 MHz, CDCl3): d = 15.2
rac-(1R,3aS,6R,6aS)-1,6-di-(4-Bromobenzyl)-6a-hydroxyhexahydropenta-
lene-3a-carboxylic acid (55): As for a general procedure D, reaction of 52
(50 mg, 0.089 mmol, 1 equiv) in THF (2.0 mL) and H2O (1.92 mL,
107 mmol, 1200 equiv) with (0.1m in THF, 7.1 mL, 0.710 mmol, 8 equiv)
after column chromatography on silica gel, eluting with a gradient of
20% ethyl acetate in petroleum ether (40–608C) gave 55 (23 mg,
1
0.045 mmol, 54%) as a white solid. M.p. 108–1108C; H NMR (400 MHz,
CDCl3): d = 1.15–1.35 (m, 2H, 2H from CH2), 1.56 (m, 3H, 3H from
CH2), 1.65–1.75 (m, 1H, 1H from CH2), 1.93–2.03 (m, 1H, CH), 2.04–
2.17 (m, 2H, 1H from CH2, CH), 2.41–2.51 (m, 2H, 1H from CH2, 1H
from ArCH2), 2.56 (dd, 1H, J=13.9, 11.3 Hz, 1H from ArCH2), 3.02 (dd,
1H, J=13.9, 2.5 Hz, 1H from ArCH2), 3.24 (dd, 1H, J=12.9, 3.0 Hz, 1H
from ArCH2), 7.09 (dd, 4H, J=8.3, 3.0 Hz, 4 ꢂ ArH), 7.42 (dd, 4H, J=
8.3, 2.0 Hz, 4 ꢂ ArH); 13C NMR (100 MHz, CDCl3): d = 27.4 (CH2),
31.8 (CH2), 34.8 (CH2), 35.2 (2 ꢂ ArCH), 35.9 (2 ꢂ ArCH), 36.0 (CH2),
47.9 (CH), 55.2 (CH), 64.0 (Cq), 92.1 (Cq), 119.7 (ArCq), 119.8 (ArCq),
130.5 (2 ꢂ ArCH), 130.6 (2 ꢂ ArCH), 131.4 (2 ꢂ ArCH), 131.5 (2 ꢂ
ArCH), 140.2 (ArCq), 140.9 (ArCq), 180.6 (C=O); IR (neat): nmax = 3040
(br. OH), 2928, 2859, 1896, 1693 (C=O), 1486, 1453, 1403, 1262, 1095,
1070, 1010, 841, 792, 741, 668 cmÀ1; MS (ESÀ): m/z (%): calcd for
C23H25O3: 06.9989; found: 506.9998 [MÀH]+.
(CH3), 22.8 (CHCH3), 23.8 (CHCH3), 25.2 (CHACHTUNGRTNEUNG(CH3)2), 27.6 (CH2), 29.6
(CH2), 41.8 (CH2), 43.2 (CHCH3), 52.4 (OCH3), 60.2 (Cq), 171.8
(COOCH3), 215.7 ppm (C=O); IR (neat): nmax = 2956, 2851, 2854, 1750
(C=O), 1728 (C=O), 1460, 1214, 1161, 1011, 967, 723 cmÀ1; MS (ES+):
m/z: calcd for C12H20O3Na: 235.1305; found: 235.1305 [M+Na]+.
rac-(1S,8S)-8-Hydroxy-bicycloACTHUNRTGNEUNG[3.2.1]octane-1-carboxylic acid (50): To a
Acknowledgements
stirred solution of 49 (25 mg, 0.112 mmol, 1 equiv) in THF (2.0 mL) and
H2O (2.2 mL, 134 mmol, 1200 equiv) was added SmI2 (0.1m in THF,
8.93 mL, 0.893 mmol, 8 equiv) dropwise using a syringe pump over 1
hour. After decolorization of the reaction mixture, the flask was opened
to air and saturated aqueous sodium chloride (10 mL) and tartaric acid
(50 mg) was added. The aqueous phase was extracted with ethyl acetate
(3ꢂ15 mL) and the combined organic phases dried (Na2SO4) and concen-
trated in vacuo. Purification by column chromatography on silica gel,
eluting with a gradient of 40% ethyl acetate in hexane gave 50 (10 mg,
0.060 mmol, 54%) as a white solid. M.p. 109–1118C (ethyl acetate);
We thank AstraZeneca (CASE award to K.D.C.), CNPq (Conselho Na-
cional de Desenvolvimento Cientifico e Tecnonologico) (Fellowship to
J.M.), EC (Marie-Curie Fellowship to G.G.), EPSRC (project student-
ship, B.S.), University of Messina, Italy (Fellowship to S.D.G) and the
University of Manchester. We also thank Malcolm Spain for preliminary
studies and the Nuffield Foundation for the award of an Undergraduate
Bursary.
1H NMR (400 MHz, CDCl3): d
= 1.20–1.29 (m, 1H, 1H from CH2),
1.47–1.69 (m, 4H, 2 ꢂ CH2), 1.73–1.89 (m, 2H, CH2), 1.90–2.01 (m, 2H,
CH2), 2.06–2.16 (m, 1H, 1H from CH2), 2.19–2.26 (m, 1H, CHCHOH),
4.17 ppm (d, 1H, J=5.3 Hz, CHOH); 13C NMR (100 MHz, CDCl3): d =
17.6 (CH2), 23.4 (CH2), 23.6 (CH2), 27.3 (CH2), 28.7 (CH2), 37.6
(CHCHOH), 50.4 (Cq), 74.5 (CHOH), 182.4 ppm (C=O); IR (evap. film):
nmax = 3422 (br. OH), 2925, 2871, 1703 (C=O), 1694 (C=O), 1454, 1291,
[1] Metal-mediated radical reactions: a) A. Gansꢃuer, H. Bluhm, Chem.
Rev. 2000, 100, 2771. Recent reviews on the use of SmI2 in synthesis:
b) T. Skrydstrup, Angew. Chem. 1997, 109, 355; Angew. Chem. Int.
Ed. Engl. 1997, 36, 345; c) G. A. Molander, C. R. Harris, Tetrahe-
dron 1998, 54, 3321; d) H. B. Kagan, J. L. Namy in Lanthanides:
Chemistry and Use in Organic Synthesis (Ed.: S. Kobayashi), Spring-
er, Berlin, 1999, p. 155; e) P. G. Steel, J. Chem. Soc. Perkin Trans. 1
2001, 2727; f) H. B. Kagan, Tetrahedron 2003, 59, 10351; g) A.
1187, 1143, 1096, 1064 cmÀ1
; MS (ES+): m/z: calcd for C9H13O3:
169.0865; found: 169.0863 [MÀH]+.
10248
www.chemeurj.org
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 10240 – 10249

Selective Reductions by Using SmI2 and H2O
FULL PAPER
Dahlꢄn, G. Hilmersson, Eur. J. Inorg. Chem. 2004, 3393; h) D. J. Ed-
monds, D. Johnston, D. J. Procter, Chem. Rev. 2004, 104, 3371; i) K.
Gopalaiah, H. B. Kagan, New J. Chem. 2008, 32, 607; j) K. C. Nico-
laou, S. P. Ellery, J. S. Chen, Angew. Chem. 2009, 121, 7276; Angew.
Chem. Int. Ed. 2009, 48, 7140; k) D. J. Procter, R. A. Flowers II, T.
Skrydstrup, Organic Synthesis using Samarium Diiodide: A Practical
Guide; RSC, Cambridge, 2010.
[10] H. Farran, S. Hoz, Org. Lett. 2008, 10, 4875.
[11] a) J. Cossy has described the radical cyclization of unsaturated
esters by using sodium–ammonia but proposes that radicals at a
lower oxidation state are involved: J. Cossy, B. Gille, V. Bellosta, J.
Org. Chem. 1998, 63, 3141; b) Srikrishna has reported the anionic
cyclization of unsaturated esters by using lithium–ammonia: A. Srik-
rishna, S. S. V. Ramasastry, Tetrahedron Lett. 2004, 45, 379; c) for an
imide–alkene cyclization mediated by SmI2, see: R. H. Taaning, L.
Thim, J. Karaffa, A. G. CampaÇa, A-M. Hansen, T. Skrydstrup, Tet-
rahedron 2008, 64, 11884.
[2] a) L. A. Duffy, H. Matsubara, D. J. Procter, J. Am. Chem. Soc. 2008,
130, 1136; b) D. Parmar, L. A. Duffy, D. V. Sadasivam, H. Matsu-
bara, P. A. Bradley, R. A. Flowers II, D. J. Procter, J. Am. Chem.
Soc. 2009, 131, 15467.
[3] G. Guazzelli, S. De Grazia, K. D. Collins, H. Matsubara, M. Spain,
D. J. Procter, J. Am. Chem. Soc. 2009, 131, 7214.
[4] a) B. Chen, Heterocycles 1991, 32, 529; b) H. McNab, Chem. Soc.
Rev. 1978, 7, 345.
[5] M. O. Polla, L. Tottie, C. Nordꢄn, M. Linschoten, D. Mꢅsil, S.
Trumpp-Kallmeyer, I. R. Aukrust, R. Ringom, K. H. Holm, S. M.
Neset, M. Sandberg, J. Thurmond, P. Yu, G. Hategan, H. Anderson,
Bioorg. Med. Chem. 2004, 12, 1151.
[12] See the Supporting Information for X-ray crystal structures and
CCDC numbers.
[13] For recent discussions of radical versus anionic cyclizations, see:
a) W. F. Bailey, M. J. Mealy, K. B. Wiberg, Org. Lett. 2002, 4, 791,
and references therein; b) S. D. Rychnovsky, T. Hata, A. I. Kim,
A. J. Buckmelter, Org. Lett. 2001, 3, 807. See also reference [11b].
[14] A. Dahlꢄn, G. Hilmersson, Tetrahedron Lett. 2001, 42, 5565, and ref-
erences [6a] and [7b].
[15] A. L. J. Beckwith, Tetrahedron 1981, 37, 3073.
[6] a) E. Hasegawa, D. P. Curran, J. Org. Chem. 1993, 58, 5008. Recent
studies on the use of H2O with SmI2: b) A. Dahlꢄn, G. Hilmersson,
B. W. Knettle, R. A. Flowers II, J. Org. Chem. 2003, 68, 4870; c) A.
Tarnopolsky, S. Hoz, Org. Biomol. Chem. 2007, 5, 3801.
[7] a) P. R. Chopade, E. Prasad, R. A. Flowers II, J. Am. Chem. Soc.
2004, 126, 44; b) E. Prasad, R. A. Flowers II, J. Am. Chem. Soc.
2005, 127, 18093; c) R. J. Enemaerke, K. Daasbjerg, T. Skrydstrup,
Chem. Commun. 1999, 343; d) M. Shabangi, R. A. Flowers II, Tetra-
hedron Lett. 1997, 38, 1137.
[8] Axial radicals are preferred due to an anomeric effect. For selected
examples, see: a) V. Malatesta, K. U. Ingold, J. Am. Chem. Soc.
1981, 103, 609; b) B. Giese, J. Dupuis, Tetrahedron Lett. 1984, 25,
1349; c) T. Cohen, M. Bhupathy, Acc. Chem. Res. 1989, 22, 152;
d) D. Crich, L. B. L. Lim, J. Chem. Soc. Perkin Trans. 1 1991, 2209.
See also reference [13b].
[16] Radical cyclizations tend to form cis-fused bicyclic products. For dis-
cussions, see: a) D. L. J. Clive, D. R. Cheshire, L. Set, J. Chem. Soc.
Chem. Commun. 1987, 353; b) D. L. J. Clive, H. W. Manning,
T. L. B. Boivin, M. H. D. Postema, J. Org. Chem. 1993, 58, 6857.
[17] For selected examples of reversible metal-mediated radical cycliza-
tions, see: a) D. P. Curran, T. M. Morgan, C. E. Schwartz, B. B.
Snider, M. A. Dombroski, J. Am. Chem. Soc. 1991, 113, 6607; b) K.
Sung, Y. Y. Wang, J. Org. Chem. 2003, 68, 2771.
[18] For SmI2-mediated transannular cyclizations involving conventional
radical anions derived from ketones, see: G. A. Molander, B. Czakꢆ,
M. Rheam, J. Org. Chem. 2007, 72, 1755.
[19] No other diastereoisomers were isolated from the cyclizations of
substrates 51–53.
[9] Calculated relative reaction energies suggest that the degree of sub-
stitution on the cyclic 1,3-diesters does not affect the ease of reduc-
tion significantly. See reference [3].
Received: March 11, 2010
Published online: July 19, 2010
Chem. Eur. J. 2010, 16, 10240 – 10249
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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